For new drug approval, "substantial evidence" of efficacy from adequate and well-controlled investigations is required. Evidence from multiple clinical trials is usually submitted, but robust results from a single multi-center trial have been accepted. In your deliberations of the following questions, consider whether the results from trials fulfill the regulatory requirement.

1. Study 010 in breast cancer and myeloma

In Study 010, 44% of Aredia patients had an SRE on study versus 46% of Zometa patients. Using the conservative two-95% confidence interval method, FDA calculates that Zometa retains at least 49% of Aredia' s efficacy (demonstrated historically in comparison to placebo).

a. Do other studies (011 and 039) provide supportive evidence for Zometa's efficacy in breast cancer and myeloma?

b. Is there substantial evidence from adequate and well-controlled investigations of Zometa (4 mg) efficacy in breast cancer and myeloma?

b. Is there substantial evidence of Zometa (4 mg) efficacy in prostate cancer from adequate and well-controlled investigations?

3. Study 011 in other solid tumors

a. Analyses from both the 4 mg and 8 mg Zometa arms of study 011 support the efficacy of Zometa. Do you agree with FDA that these results provide substantial evidence of Zometa (4 mg) efficacy in the population studied?

This indication infers treatment is indicated for patients with bone metastases from all solid tumors irrespective of the primary tumor. Do you agree with this proposed indication? Please provide suggestions for wording of the indication section or the clinical trials section of the Zometa labeling with regard to this issue.